GMl gangliosidosis is a deficiency of GMl ganglioside beta-galactosidase, and associated with intraneuronal storage of GMl ganglioside. Two breeds of mutant dogs with GMl gangliosidosis have been made available to me at New England Medical Center. Clinically, these mutants resemble human GMl gangliosidoses of infantile and juvenile onset. Preliminary studies have characterized the biochemical and pathological abnormalities in these animals. The beta-galactosidase enzyme has been purified from normal dog liver. Synthetic oligonucleotide probes from a polypeptide fragment of that enzyme in addition to a human cDNA fragment encoding beta- galactosidase have been designed. The goal of the proposed research is to identify and compare the molecular defects in canine and human GMl gangliosidosis. The specific goals are: 1) to isolate and characterize cDNA clones encoding canine GMl ganglioside beta-galactosidase; confirm the validity of the presumed cDNA clone encoding canine GMl ganglioside beta-galactosidase; 3) to characterize the mRNAs corresponding to mutant canine and human GMl ganglioside beta-galactosidase; 4) to characterize the human beta- galactosidase gene structure including sequences around the exon-intron junctions. These planned studies, made possible by my background in clinical neurology and neurochemistry, will provide me with molecular genetic tools to be used to investigate the pathophysiology of and potential therapies for the lysosomal storage disorders.
| Sena-Esteves, M; Camp, S M; Alroy, J et al. (2000) Correction of acid beta-galactosidase deficiency in GM1 gangliosidosis human fibroblasts by retrovirus vector-mediated gene transfer: higher efficiency of release and cross-correction by the murine enzyme. Hum Gene Ther 11:715-27 |
| Kaye, E M; Doll, R F; Natowicz, M R et al. (1994) Pelizaeus-Merzbacher disease presenting as spinal muscular atrophy: clinical and molecular studies. Ann Neurol 36:916-9 |
| Kaye, E M; Alroy, J; Raghavan, S S et al. (1992) Dysmyelinogenesis in animal model of GM1 gangliosidosis. Pediatr Neurol 8:255-61 |
| Kaye, E M; Ullman, M D; Kolodny, E H et al. (1992) Possible use of CSF glycosphingolipids for the diagnosis and therapeutic monitoring of lysosomal storage diseases. Neurology 42:2290-4 |
